Pharmacology of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

1. Introduction/Overview

Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a chemically diverse group of therapeutic agents united by their shared pharmacological properties of analgesia, antipyresis, and anti-inflammatory activity. These drugs represent one of the most widely prescribed and utilized classes of medications globally, available both by prescription and as over-the-counter preparations. Their clinical importance stems from their efficacy in managing a broad spectrum of conditions characterized by pain, fever, and inflammation, ranging from minor musculoskeletal injuries to chronic arthritic diseases.

The therapeutic relevance of NSAIDs is underscored by their role as first-line agents in the symptomatic management of pain and inflammation. They are fundamental in the treatment paradigm for osteoarthritis, rheumatoid arthritis, acute gout, dysmenorrhea, and various soft tissue injuries. Furthermore, certain NSAIDs, notably aspirin, possess unique antiplatelet properties that are cornerstone therapies in the secondary prevention of cardiovascular and cerebrovascular events. The widespread use of these agents necessitates a thorough understanding of their pharmacology, as their benefits are counterbalanced by a well-characterized profile of potential adverse effects, particularly involving the gastrointestinal tract, kidneys, and cardiovascular system.

Learning Objectives

• Describe the molecular mechanism of action of NSAIDs, focusing on the inhibition of cyclooxygenase (COX) isoforms and the subsequent impact on prostanoid biosynthesis.
• Classify major NSAIDs based on chemical structure, COX selectivity, and pharmacokinetic properties, and relate these characteristics to clinical use.
• Analyze the pharmacokinetic principles governing NSAID absorption, distribution, metabolism, and excretion, and apply this knowledge to dosing regimens and special populations.
• Evaluate the major therapeutic applications of NSAIDs, balancing their efficacy against the risk of common and serious adverse effects across different organ systems.
• Formulate appropriate clinical considerations for NSAID use, including the management of drug interactions, contraindications, and administration in patients with comorbidities or in specific physiological states such as pregnancy.

2. Classification

NSAIDs can be classified according to several schemas, including chemical structure, pharmacokinetic half-life, and selectivity for cyclooxygenase enzyme isoforms. A comprehensive classification integrates these aspects to inform clinical utility and safety profiles.

Chemical Classification

The chemical backbone of an NSAID is a primary determinant of its pharmacological properties. Major chemical classes include:

• Salicylates: Exemplified by acetylsalicylic acid (aspirin). This class is characterized by irreversible acetylation of the COX enzyme, a property unique to aspirin among NSAIDs.
• Propionic Acid Derivatives: A large and commonly used class including ibuprofen, naproxen, ketoprofen, and flurbiprofen. These agents are often employed as first-line therapies for mild to moderate pain and inflammation.
• Acetic Acid Derivatives: This group includes diclofenac, ketorolac, and indomethacin. Diclofenac and indomethacin are potent anti-inflammatory agents, while ketorolac is notable for its potent analgesic properties, suitable for short-term management of moderate to severe acute pain.
• Enolic Acid (Oxicam) Derivatives: Piroxicam and meloxicam belong to this class. They typically possess long elimination half-lives, permitting once-daily dosing.
• Fenamic Acid Derivatives (Fenamates): Mefenamic acid and meclofenamate are members of this class, sometimes used for dysmenorrhea.
• Non-Acidic Compounds: Nabumetone is a prodrug that is metabolized to an active acidic form. Celecoxib is a sulfonamide and falls under the coxib subclass.
• Selective COX-2 Inhibitors (Coxibs): Celecoxib, etoricoxib, and parecoxib (a parenteral prodrug of valdecoxib). These agents were developed to provide anti-inflammatory and analgesic effects with reduced risk of gastrointestinal ulceration.

Classification by COX Selectivity

Based on their relative inhibition of the constitutive COX-1 and inducible COX-2 isoforms, NSAIDs are often categorized as:

• Non-Selective COX Inhibitors: The majority of traditional NSAIDs (e.g., ibuprofen, naproxen, diclofenac, indomethacin) inhibit both COX-1 and COX-2 with varying degrees of preference but without absolute selectivity.
• Preferential COX-2 Inhibitors: Drugs like meloxicam and etodolac show a greater inhibitory potency for COX-2 than for COX-1 at therapeutic doses.
• Selective COX-2 Inhibitors (Coxibs): Celecoxib and etoricoxib exhibit high selectivity for the COX-2 isoform, with minimal effect on COX-1 at their standard clinical doses.

Classification by Elimination Half-Life

• Short-Acting (t_1/2 < 6 hours): Ibuprofen, ketoprofen, diclofenac. These often require dosing three to four times daily for sustained anti-inflammatory effect.
• Intermediate-Acting (t_1/2 6-12 hours): Naproxen.
• Long-Acting (t_1/2 > 12 hours): Piroxicam, celecoxib, meloxicam, nabumetone. These are suitable for once-daily administration, which may improve adherence but can also prolong the duration of adverse effects following discontinuation.

3. Mechanism of Action

The primary mechanism of action for all NSAIDs is the inhibition of the cyclooxygenase (COX) enzyme, also known as prostaglandin-endoperoxide synthase (PTGS). This enzyme catalyzes the conversion of arachidonic acid, released from membrane phospholipids by phospholipase A₂, into prostaglandin G₂ (PGG₂) and subsequently to prostaglandin H₂ (PGH₂). PGH₂ serves as the precursor for a variety of biologically active prostanoids, including prostaglandins (e.g., PGE₂, PGF_2α), prostacyclin (PGI₂), and thromboxane A₂ (TXA₂). The inhibition of prostanoid synthesis underlies the therapeutic and many of the adverse effects of NSAIDs.

Cyclooxygenase Isoforms: COX-1 and COX-2

Two major isoforms of COX are recognized:

• COX-1: This isoform is constitutively expressed in most tissues, including platelets, the gastric mucosa, vascular endothelium, and kidneys. It is considered a “housekeeping” enzyme involved in physiological functions such as gastric cytoprotection (via mucus and bicarbonate secretion), platelet aggregation (via TXA₂), and regulation of renal blood flow.
• COX-2: This isoform is primarily inducible by inflammatory stimuli (e.g., cytokines, growth factors) at sites of tissue injury. Its expression is upregulated in inflamed tissues, contributing to the pain, swelling, and fever associated with inflammation. COX-2 is also constitutively expressed in certain tissues, including the brain, kidney, and reproductive tract, where it participates in normal physiological processes.

Molecular and Cellular Mechanisms

NSAIDs bind reversibly (or irreversibly, in the case of aspirin) to the active site of the COX enzyme, blocking access to the substrate arachidonic acid. The specific interactions within the enzyme’s binding pocket determine selectivity and potency.

• Analgesic Effect: Mediated primarily through the inhibition of prostaglandin synthesis, particularly PGE₂ and PGI₂, in peripheral tissues and the central nervous system. These prostaglandins sensitize nociceptors to mechanical and chemical stimuli (e.g., bradykinin, histamine), lowering their activation threshold. By reducing prostaglandin production, NSAIDs elevate the pain threshold.
• Anti-inflammatory Effect: Results from decreased formation of prostaglandins and other prostanoids at the site of inflammation. PGE₂ and PGI₂ are potent vasodilators and contribute to edema formation. Their inhibition reduces vasodilation, swelling, and the associated pain from tissue pressure.
• Antipyretic Effect: Fever is mediated by pyrogenic cytokines (e.g., interleukin-1) that stimulate the synthesis of PGE₂ in the hypothalamus, thereby raising the body’s thermoregulatory set point. NSAIDs inhibit hypothalamic COX, reducing PGE₂ levels and normalizing the set point, leading to vasodilation and heat loss.
• Antiplatelet Effect (Aspirin-specific): Aspirin irreversibly acetylates a serine residue (Ser529 in human COX-1, Ser516 in COX-2) within the COX enzyme. In anucleate platelets, which cannot synthesize new protein, this results in a permanent loss of TXA₂ production for the lifespan of the platelet (≈7-10 days). This unique mechanism is the basis for aspirin’s use in cardiovascular prophylaxis. Other NSAIDs reversibly inhibit platelet COX-1, leading to a transient antiplatelet effect that lasts only while the drug is present at sufficient concentration.

4. Pharmacokinetics

The pharmacokinetic profiles of NSAIDs are diverse but share common features due to their generally acidic nature. Understanding these parameters is crucial for predicting onset and duration of action, potential for drug interactions, and accumulation in special populations.

Absorption

Most NSAIDs are weak organic acids with pK_a values typically ranging from 3 to 5. In the acidic environment of the stomach, they exist predominantly in their non-ionized, lipid-soluble form, which favors passive diffusion across gastric membranes. However, due to the much larger surface area of the small intestine, the primary site of absorption for most orally administered NSAIDs is the duodenum. Absorption is generally rapid and complete, with peak plasma concentrations (C_max) achieved within 1 to 4 hours. Food can delay the rate of absorption (increasing T_max) but usually does not significantly reduce the total extent of absorption (AUC), except for specific agents like nabumetone. Some NSAIDs, such as ketorolac and diclofenac, are available in parenteral formulations for rapid onset of action in acute pain settings.

Distribution

Following absorption, NSAIDs are highly bound to plasma albumin (>95-99%). This high degree of protein binding has significant clinical implications. First, it limits the volume of distribution, typically to approximately 0.1-0.2 L/kg. Second, it creates a high potential for protein-binding displacement interactions with other highly albumin-bound drugs (e.g., warfarin, sulfonylureas, phenytoin), which can transiently increase the free fraction of both drugs. NSAIDs distribute widely into synovial fluid, inflamed tissues, and the central nervous system. The concentration in synovial fluid may be lower than in plasma but often declines more slowly, which may contribute to a longer duration of clinical effect than predicted by plasma half-life.

Metabolism

Hepatic metabolism is the principal route of elimination for most NSAIDs. The major metabolic pathways involve Phase I reactions, primarily oxidation via the cytochrome P450 (CYP) system, and Phase II conjugation reactions (glucuronidation, sulfation). Specific CYP isoforms involved include CYP2C9 (important for ibuprofen, diclofenac, celecoxib, and many others) and CYP2C19. Genetic polymorphisms in these enzymes, particularly CYP2C9, can lead to inter-individual variability in drug metabolism and response. Some NSAIDs, like naproxen, undergo metabolism with minimal CYP involvement. Nabumetone is a unique non-acidic prodrug that is hepatically metabolized to its active form, 6-methoxy-2-naphthylacetic acid. Celecoxib is metabolized primarily by CYP2C9, with a minor role for CYP3A4.

Excretion

Metabolites, and to a lesser extent unchanged drug, are excreted predominantly in the urine. Renal excretion involves both glomerular filtration of the unbound fraction and active tubular secretion. A small percentage is excreted in the bile. The elimination half-life (t_1/2) varies widely among NSAIDs, from approximately 1-2 hours for ibuprofen to over 50 hours for piroxicam. This parameter is a key determinant of dosing frequency. For drugs with short half-lives given for anti-inflammatory effect, dosing must be frequent enough to maintain consistent enzyme inhibition. It is important to note that the relationship between plasma half-life and duration of clinical effect is not always linear, partly due to drug persistence at the site of action (e.g., synovial fluid).

5. Therapeutic Uses/Clinical Applications

NSAIDs are employed for a vast array of clinical conditions where reduction of pain, fever, or inflammation is desired. Their use is primarily symptomatic and does not alter the underlying disease course in most chronic conditions, with the exception of aspirin in atherothrombosis.

Approved Indications

• Musculoskeletal Disorders: This represents the most common indication. NSAIDs are first-line therapy for the pain and inflammation of osteoarthritis and are used as symptomatic agents in rheumatoid arthritis, ankylosing spondylitis, and acute gouty arthritis. In gout, NSAIDs like indomethacin or naproxen are effective for acute attacks.
• Acute Pain Management: Widely used for postoperative pain, dental pain, musculoskeletal injuries (sprains, strains), and renal colic. Ketorolac is particularly valued for its potent analgesic efficacy, comparable to some opioids, for short-term use.
• Dysmenorrhea: NSAIDs are highly effective in treating primary dysmenorrhea by inhibiting the uterine production of prostaglandins, which mediate painful uterine contractions.
• Headache: Including tension-type headaches and migraines. Ibuprofen and naproxen are commonly used, and specific formulations of aspirin are also indicated for migraine.
• Antipyresis: Used to reduce fever in adults and children, though caution is advised in pediatric populations due to the association between aspirin and Reye’s syndrome.
• Cardiovascular Prophylaxis (Aspirin): Low-dose aspirin (75-325 mg daily) is indicated for the secondary prevention of myocardial infarction, stroke, and other thrombotic events in high-risk patients, based on its irreversible antiplatelet effect.

Off-Label and Evolving Uses

• Pericarditis: High-dose aspirin or other NSAIDs (e.g., ibuprofen) are used as first-line therapy to reduce inflammation in acute pericarditis.
• Patent Ductus Arteriosus (PDA): Intravenous ibuprofen or indomethacin is used to promote closure of a hemodynamically significant PDA in preterm neonates.
• Cancer Prevention: Long-term administration of aspirin has been associated with a reduced risk of colorectal cancer and possibly other cancers in epidemiological studies, though this is not a formal indication and risks must be carefully weighed.
• Prevention of Postoperative Heterotopic Ossification: Indomethacin is sometimes used following orthopedic procedures, such as total hip arthroplasty.

6. Adverse Effects

The inhibition of physiologically important prostaglandins underlies the significant adverse effect profile associated with NSAID use. The risk and type of adverse effects are influenced by the specific drug, dose, duration of therapy, and patient-specific factors such as age and comorbidities.

Common Side Effects

• Gastrointestinal (GI): The most frequent adverse effects involve the GI tract, ranging from dyspepsia, nausea, and abdominal pain to more serious complications. The pathogenesis involves dual mechanisms: a direct topical irritant effect on the gastric mucosa and, more importantly, the systemic inhibition of COX-1-derived prostaglandins (PGE₂ and PGI₂) that maintain mucosal blood flow, stimulate mucus and bicarbonate secretion, and inhibit gastric acid secretion. The risk of endoscopic ulcers is approximately 15-30% with chronic use, and the annual risk of serious GI complications (bleeding, perforation, obstruction) is 1-4%.
• Renal: Prostaglandins (particularly PGE₂ and PGI₂) are crucial for maintaining renal blood flow, especially in states of decreased effective circulating volume (e.g., heart failure, cirrhosis, dehydration, chronic kidney disease). NSAID-induced inhibition can lead to reversible renal vasoconstriction, reduced glomerular filtration rate (GFR), and fluid and electrolyte disturbances (sodium retention, hyperkalemia, edema). Acute interstitial nephritis, manifesting as acute kidney injury with proteinuria and hematuria, is an idiosyncratic reaction associated with several NSAIDs.

Serious/Rare Adverse Reactions

• Cardiovascular (CV): All NSAIDs, with the possible exception of naproxen, have been associated with an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke. The proposed mechanism involves an imbalance between prostacyclin (PGI₂, a vasodilator and inhibitor of platelet aggregation) and thromboxane A₂ (TXA₂, a vasoconstrictor and platelet aggregator). COX-2 inhibitors and non-selective NSAIDs suppress vascular endothelial PGI₂ production while leaving platelet TXA₂ generation unaffected (or transiently affected, in the case of non-aspirin NSAIDs). This pro-thrombotic shift is believed to increase CV risk. The risk appears to be dose-dependent and duration-dependent, and is highest in patients with established CV disease.
• Hepatic: Elevations in serum transaminases (ALT, AST) are common but often transient and asymptomatic. Rarely, NSAIDs can cause clinically significant hepatotoxicity, ranging from hepatitis to fulminant hepatic failure. Diclofenac has a higher reported incidence of hepatotoxicity compared to other NSAIDs.
• Hypersensitivity Reactions: NSAIDs can induce a range of hypersensitivity reactions. Aspirin-exacerbated respiratory disease (AERD), also known as Samter’s triad, involves asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to COX-1 inhibitors. NSAIDs can also cause urticaria, angioedema, and anaphylaxis. Cross-reactivity among NSAIDs is common, particularly among non-selective inhibitors.
• Central Nervous System: Headache, dizziness, tinnitus, and cognitive dysfunction can occur. Aseptic meningitis is a rare but serious reaction linked particularly to ibuprofen and other NSAIDs.
• Hematologic: All non-aspirin NSAIDs reversibly impair platelet aggregation, potentially prolonging bleeding time. Aplastic anemia and agranulocytosis are rare idiosyncratic reactions.

Black Box Warnings

In many regulatory jurisdictions, NSAIDs carry boxed warnings concerning:

• Cardiovascular Risk: Stating that NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use and is higher in patients with CV disease or risk factors.
• Gastrointestinal Risk: Warning of the risk of serious GI adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms, especially in the elderly.

7. Drug Interactions

The pharmacokinetic and pharmacodynamic properties of NSAIDs create a substantial potential for clinically significant drug interactions.

Major Pharmacodynamic Interactions

• Anticoagulants (e.g., Warfarin, DOACs) and Antiplatelets (e.g., Clopidogrel): NSAIDs increase the risk of bleeding through multiple mechanisms: their antiplatelet effect (impaired aggregation), potential to cause GI ulceration, and pharmacokinetic interactions (protein-binding displacement with warfarin). The concurrent use of NSAIDs with warfarin requires careful monitoring of the International Normalized Ratio (INR).
• Other Antihypertensives: NSAIDs can antagonize the effects of diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and beta-blockers. The mechanism involves inhibition of renal prostaglandin-mediated vasodilation and promotion of sodium retention, which can lead to a clinically significant rise in blood pressure and potentially precipitate heart failure.
• Corticosteroids (e.g., Prednisone): Concomitant use significantly increases the risk of GI ulceration and bleeding due to additive mucosal injury.
• Selective Serotonin Reuptake Inhibitors (SSRIs): SSRIs impair platelet function and may increase the risk of upper GI bleeding when combined with NSAIDs.

Major Pharmacokinetic Interactions

• Protein-Binding Displacement: As highly albumin-bound drugs, NSAIDs can displace other bound drugs (e.g., warfarin, phenytoin, sulfonylureas), transiently increasing their free, active concentration. This effect is usually temporary as the increased free fraction is metabolized, but it can be clinically significant for drugs with a narrow therapeutic index.
• Cytochrome P450 Interactions: Some NSAIDs are substrates or inhibitors of CYP enzymes. For example, fluconazole (a CYP2C9 inhibitor) can increase plasma concentrations of celecoxib, ibuprofen, and diclofenac. Conversely, NSAIDs are rarely potent CYP inhibitors themselves.
• Lithium: NSAIDs reduce renal clearance of lithium by inhibiting prostaglandin-mediated mechanisms in the kidney, potentially leading to lithium toxicity. Serum lithium levels require close monitoring if an NSAID is initiated or discontinued.
• Methotrexate: High-dose methotrexate used in oncology can have its renal clearance reduced by NSAIDs, increasing the risk of methotrexate toxicity (myelosuppression, mucositis). This interaction is less concerning with the low-dose methotrexate used in rheumatoid arthritis, but caution is still advised.

Contraindications

Absolute contraindications to NSAID use include:

• Active peptic ulcer disease or recent GI bleeding.
• History of hypersensitivity reactions (e.g., asthma, urticaria, anaphylaxis) to aspirin or any other NSAID.
• Severe renal impairment or active kidney disease.
• Third trimester of pregnancy (risk of premature closure of the fetal ductus arteriosus and oligohydramnios).
• Coronary artery bypass graft (CABG) surgery peri-operative period (due to increased risk of cardiovascular and renal complications).

8. Special Considerations

Pregnancy and Lactation

NSAID use during pregnancy requires careful risk-benefit assessment. During the first and second trimesters, NSAIDs are generally not considered major teratogens but should be used at the lowest effective dose for the shortest duration. Use in the third trimester (after 30 weeks gestation) is contraindicated. Inhibition of prostaglandin synthesis can cause premature closure of the fetal ductus arteriosus, leading to persistent pulmonary hypertension of the newborn. It may also result in oligohydramnios (reduced amniotic fluid) due to decreased fetal renal function. During lactation, most NSAIDs are considered compatible as they are excreted in breast milk in very low concentrations. Ibuprofen and naproxen are often preferred choices due to extensive safety data.

Pediatric Considerations

Ibuprofen and naproxen are commonly used in children for fever and pain. Dosing is based on body weight. A critical historical consideration is the association between aspirin use in children and adolescents with viral illnesses (e.g., influenza, chickenpox) and the development of Reye’s syndrome, a rare but severe condition characterized by acute encephalopathy and liver failure. Consequently, aspirin is contraindicated in this population for antipyresis. Pediatric formulations must be used accurately to avoid dosing errors.

Geriatric Considerations

Older adults are at significantly increased risk for NSAID-related adverse effects due to age-related pharmacokinetic changes (e.g., reduced renal clearance, altered volume of distribution), increased prevalence of comorbidities (CV disease, renal impairment, GI history), and polypharmacy. The risk of GI bleeding, acute kidney injury, hypertension, and drug interactions is markedly elevated. If NSAID use is necessary in this population, the general principle is to “start low and go slow,” using the lowest effective dose for the shortest possible duration. Concomitant use of a gastroprotective agent (e.g., a proton pump inhibitor) is strongly recommended.

Renal and Hepatic Impairment

In patients with renal impairment, NSAIDs should be used with extreme caution or avoided altogether, especially if the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73m². These patients are highly dependent on prostaglandins to maintain renal perfusion. NSAIDs can precipitate acute kidney injury and exacerbate fluid retention and hyperkalemia. Short-acting NSAIDs may be preferred over long-acting ones. In patients with hepatic impairment, NSAIDs should also be used cautiously. Reduced hepatic metabolism can lead to drug accumulation, and the compromised synthetic function may affect protein binding, increasing the free fraction of the drug. Furthermore, NSAIDs can potentially worsen portal hypertension and variceal bleeding risk. Monitoring of liver function tests is advisable during chronic therapy.

9. Summary/Key Points

• NSAIDs exert their therapeutic effects (analgesic, anti-inflammatory, antipyretic) through the inhibition of cyclooxygenase (COX) enzymes, thereby reducing the synthesis of pro-inflammatory and sensitizing prostanoids.
• The inhibition of constitutively expressed COX-1 is primarily responsible for major adverse effects, including gastrointestinal ulceration, renal impairment, and impaired platelet aggregation. Inhibition of inducible COX-2 provides therapeutic anti-inflammatory effects but may contribute to cardiovascular risk by disrupting the prostacyclin-thromboxane balance.
• Pharmacokinetic properties vary widely; key parameters include high plasma protein binding, extensive hepatic metabolism (often via CYP2C9), and renal excretion. Elimination half-life dictates dosing frequency.
• Therapeutic applications are broad, encompassing musculoskeletal disorders, acute pain, dysmenorrhea, fever, and, for aspirin, cardiovascular prophylaxis. Selection depends on the condition, desired onset/duration, and patient-specific risk factors.
• The adverse effect profile is significant and organ-specific. Major concerns include gastrointestinal bleeding, cardiovascular thrombotic events, renal toxicity, and hypersensitivity reactions. Risk is influenced by drug selectivity, dose, duration, and patient comorbidities.
• NSAIDs have a high potential for drug interactions, both pharmacodynamic (e.g., increased bleeding risk with anticoagulants, blunted effect of antihypertensives) and pharmacokinetic (e.g., protein-binding displacement, altered lithium clearance).
• Special populations require tailored approaches: avoidance in late pregnancy, caution with aspirin in children, heightened vigilance in the elderly, and extreme caution or avoidance in patients with significant renal or hepatic impairment.

Clinical Pearls

• For chronic inflammatory conditions, NSAIDs should be prescribed at an anti-inflammatory dose and frequency, often requiring regular rather than “as-needed” dosing to maintain steady-state enzyme inhibition.
• The choice between a non-selective NSAID and a selective COX-2 inhibitor involves weighing GI safety against CV risk. In patients with high GI risk and low CV risk, a COX-2 inhibitor plus a proton pump inhibitor may be appropriate. In patients with high CV risk, naproxen may be a preferred non-selective agent, though all NSAIDs should be used cautiously.
• No NSAID is completely devoid of GI or CV risk. The lowest effective dose for the shortest necessary duration should always be the goal.
• Patient education is crucial: instructing patients to take NSAIDs with food or milk to reduce GI upset, to report signs of GI bleeding (black stools, abdominal pain) or CV symptoms (chest pain, shortness of breath), and to avoid concomitant use of over-the-counter NSAIDs or aspirin without consulting a healthcare provider.
• In patients requiring both an NSAID and cardioprotective aspirin, the NSAID should be taken at least 30 minutes after or 8 hours before the immediate-release aspirin dose to avoid competitive interference with aspirin’s irreversible binding to platelet COX-1.

References

1. Fishman SM, Ballantyne JC, Rathmell JP. Bonica's Management of Pain. 5th ed. Philadelphia: Wolters Kluwer; 2018.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
7. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.